4-fluoropyrrolidine-2-carbonyl fluoride compounds and their preparative methods

Abstract

Novel 4-fluoropyrrolidine-2-carbonyl fluoride compounds as useful fluorinated intermediates are disclosed. Their preparative methods are also disclosed. Useful applications of the 4-fluoropyrrolidine-2-carbonyl fluorides are shown.

1. A 4-fluoropyrrolidine-2-carbonyl fluoride compound having a formula (I) as follows: 
       
         
           
           
               
               
           
         
         in which R is a substituted or unsubstituted alkoxycarbonyl group having 2 to 35 carbon atoms, a substituted or unsubstituted aryloxycarbonyl group having 7 to 35 carbon atoms, a substituted or unsubstituted acyl group having 1 to 35 carbon atoms, a substituted or unsubstituted alkanesulfonyl group having 1 to 35 carbon atoms, a substituted or unsubstituted arenesulfonyl group having 6 to 35 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 35 carbon atoms. 
       
     
     
       2. The 4-fluoropyrrolidine-2-carbonyl fluoride compound of  claim 1  wherein R is a substituted or unsubstituted alkoxycarbonyl group having 2 to 15 carbon atoms, a substituted or unsubstituted aryloxycarbonyl group having 7 to 15 carbon atoms, a substituted or unsubstituted acyl group having 1 to 15 carbon atoms, a substituted or unsubstituted alkanesulfonyl group having 1 to 15 carbon atoms, a substituted or unsubstituted arenesulfonyl group having 6 to 15 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 15 carbon atoms. 
     
     
       3. The 4-fluoropyrrolidine-2-carbonyl fluoride compound of  claim 1  wherein R is a substituted or unsubstituted alkoxycarbonyl group having 2 to 15 carbon atoms or a substituted or unsubstituted acyl group having 1 to 15 carbon atoms. 
     
     
       4. The 4-fluoropyrrolidine-2-carbonyl fluoride compound of  claim 1  selected from a group consisting of: (2S,4S)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(9-fluorenylmethoxycarbonyl)-cis-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(9-fluorenylmethoxycarbonyl)-trans-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(benzyloxycarbonyl)-cis-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(benzyloxycarbonyl)-trans-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(tert-butoxycarbonyl)-cis-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-(tert-butoxycarbonyl)-trans-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-chloroacetyl-cis-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-chloroacetyl-trans-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-bromoacetyl-cis-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-bromoacetyl-trans-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-iodooacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4R)—N-iodoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-iodoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2R,4S)—N-iodoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, racemic N-iodoacetyl-cis-4-fluoropyrrolidine-2-carbonyl fluoride, and racemic N-iodoacetyl-trans-4-fluoropyrrolidine-2-carbonyl fluoride. 
     
     
       5. The 4-fluoropyrrolidine-2-carbonyl fluoride compound of  claim 1  selected from a group consisting of: (2S,4S)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-chloroacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4R)—N-bromoacetyl-4-fluoropyrrolidine-2-carbonyl fluoride. 
     
     
       6. The 4-fluoropyrrolidine-2-carbonyl fluoride compound of  claim 1  selected from a group consisting of: (2S,4S)—N-(9-fluorenylmethoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(benzyloxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, (2S,4S)—N-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carbonyl fluoride, and (2S,4S)—N-(chloroacetyl)-4-fluoropyrrolidine-2-carbonyl fluoride. 
     
     
       7. A method for preparing a 4-fluoropyrrolidine-2-carbonyl fluoride compound having a formula (I) as follows: 
       
         
           
           
               
               
           
         
         the method comprising reacting a 4-hydroxypyrrolidine-2-carboxylic acid compound having a formula (II) with a fluorinating agent: 
       
       
         
           
           
               
               
           
         
         in which R is a substituted or unsubstituted alkoxycarbonyl group having 2 to 35 carbon atoms, a substituted or unsubstituted aryloxycarbonyl group having 7 to 35 carbon atoms, a substituted or unsubstituted acyl group having 1 to 35 carbon atoms, a substituted or unsubstituted alkanesulfonyl group having 1 to 35 carbon atoms, a substituted or unsubstituted arenesulfonyl group having 6 to 35 carbon atoms, a substituted or unsubstituted alkyl group having 1 to 35 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 35; and R 1  and R 2  each is independently a hydrogen atom or a SiR 3 R 4 R 5  group, in which R 3 , R 4 , and R 5  each is independently an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. 
       
     
     
       8. The method of  claim 7  wherein the fluorinating agent is a compound that undertakes a deoxo-fluorination reaction. 
     
     
       9. The method of  claim 7  wherein the fluorinating agent is selected from a group consisting of: substituted or unsubstituted phenylsulfur trifluorides, substituted (diamino)difluoromethanes, substituted α,α-difluoroalkylamines, substituted aminosulfur trifluorides, and sulfur tetrafluoride. 
     
     
       10. The method of  claim 7  wherein the fluorinating agent is a substituted or unsubstituted phenylsulfur trifluoride having a formula (III): 
       
         
           
           
               
               
           
         
         in which R a , R b , R c , R d , and R e  each is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a nitro group, or a cyano group. 
       
     
     
       11. The method of  claim 7  wherein the fluorinating agent is selected from a group consisting of phenylsulfur trifluoride, 4-methylphenylsulfur trifluoride, 4-(tert-butyl)phenylsulfur trifluoride, 4-(tert-butyl)-2,6-dimethylphenylsulfur trifluoride, 4-fluorophenylsulfur trifluoride, 4-chlorophenylsulfur trifluoride, 2,2-difluoro-1,3-dimethylimizadolidine, ClCHFCF 2 N(CH 2 CH 3 ) 2  (Yarovenko reagent), CF 3 CHFCF 2 N(CH 2 CH 3 ) 2  (Ishikawa reagent), CHF 2 CF 2 N(CH 3 ) 2 , dimethylaminosulfur trifluoride, diethylaminosulfur trifluoride, and bis(methoxyethyl)aminosulfur trifluoride. 
     
     
       12. The method of  claim 7  wherein the fluorinating agent is 4-(tert-butyl)-2,6-dimethylphenylsulfur trifluoride. 
     
     
       13. A N-haloacetyl-4-hydroxypyrrolidine-2-carboxylic acid compound having a formula (II′) as follows: 
       
         
           
           
               
               
           
         
         in which X is a halogen atom; and R 1  and R 2  each is independently a hydrogen atom or a SiR 3 R 4 R 5  group wherein R 3 , R 4 , and R 5  each is independently an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. 
       
     
     
       14. The N-haloacetyl-4-hydroxypyrrolidine-2-carboxylic acid compound of  claim 13  selected from a group consisting of: (2S,4S)—N-(chloroacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, (2S,4R)—N-(chloroacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, trimethylsilyl (2S,4S)—N-(chloroacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, trimethylsilyl (2S,4R)—N-(chloroacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, (2S,4S)—N-(bromoacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, (2S,4R)—N-(bromoacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, trimethylsilyl (2S,4S)—N-(bromoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, trimethylsilyl (2S,4R)—N-(bromoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, (2S,4S)—N-(iodoacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, (2S,4R)—N-(iodoacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, trimethylsilyl (2S,4S)—N-(iodoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, and trimethylsilyl (2S,4R)—N-(iodoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate. 
     
     
       15. The N-haloacetyl-4-hydroxypyrrolidine-2-carboxylic acid compound of  claim 13  selected from a group consisting of: (2S,4R)—N-(chloroacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, trimethylsilyl (2S,4R)—N-(chloroacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate, (2S,4R)—N-(bromoacetyl)-4-hydroxypyrrolidine-2-carboxylic acid, and trimethylsilyl (2S,4R)—N-(bromoacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate.